Is MAPT p.His754= (c.2262C>T) pathogenic?

MAPT p.His754= (c.2262C>T) is classified Likely benign in MAPT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-27). Ultra-rare (popmax 0.0374%, afr); Associated with frontotemporal dementia.

What condition is associated with MAPT p.His754= (c.2262C>T)?

MAPT p.His754= (c.2262C>T) is associated with frontotemporal dementia (ClinVar).

How common is MAPT p.His754= (c.2262C>T) in the general population?

MAPT p.His754= (c.2262C>T) is ultra-rare (popmax 0.0374%, afr) (gnomAD).

MAPT p.His754=

c.2262C>T · rs747658161 · VCV1568154

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0374%, afr)

Conditions

frontotemporal dementia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -14
Overall
CADD	0.429	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0374% African / African-American · 28/74,912 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00737% 119/1,613,822 alleles · ultra-rare exomes 101/1,461,624 · genomes 18/152,198 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0374%	2,675
Middle Eastern	0.0164%	6,084
South Asian	0.0132%	7,590
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.00602%	16,617
Admixed American	0.00333%	30,004
East Asian	0.00223%	44,900

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAPT
Protein: p.His754=
Coding: c.2262C>T
MANE Select: NM_001377265
dbSNP: rs747658161
Type: single nucleotide variant
Location: chr17:46018706 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 49.56 · 299 PDB
Residue 754: a β-strand

Full MAPT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAPT p.His754Tyr Likely pathogenic ★ ⚠ same residue
MAPT c.1999-10G>T Pathogenic ★★ same condition
MAPT c.2091+16C>T Pathogenic ★★ same condition
MAPT c.2091+3G>A Pathogenic ★★ same condition
MAPT p.Arg798Trp Pathogenic ★★ ⚠ same condition
MAPT p.Asn671Lys Pathogenic ★★ ⚠ same condition
MAPT p.Asn688= Pathogenic ★★ same condition
MAPT p.Gln728His Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mapt-p-his754 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown